The treatment of certain types of cancer can be hindered by the development of resistance in the cancer cells to anti-cancer agents targeted to the cells. Rational drug combinations offer a therapeutic opportunity to avoid development of drug resistance to targeted therapies by simultaneously targeting both the primary target and compensatory pathway(s), preventing activation of pro-survival signaling [39,40]. For example, upregulation of BCL2 or MCL1 has been shown to confer FLT3-independence to leukemia cells [4]. Simultaneous targeting of FLT3 and BCL2 or MCL1, or causing BCL2 or MCL1 down regulation, may produce a lethal effect.
Several lethal drug combination screens have recently identified rational drug combinations based on adaptive resistance mechanisms of cancer cells, such as activation of compensatory signaling pathways [40-43]. Another recent screen used a library of small molecule kinase inhibitors to identify signaling pathway dependencies in primary acute leukemia patient cells, based on inclusion of the common targets of kinase inhibitors to which the sample was sensitive and exclusion of the targets of inhibitors to which the sample was not sensitive [44].
Recent reports have demonstrated that the potent antimalarial drug artemisinin and its semisynthetic derivatives have the potential to be repurposed for use in anti-leukemic regimens. Two artemisinin derivatives, Artesunate (AS) and artemisinin-derived trioxane diphenylphosphate dimer 838 (ART-838), have demonstrated antineoplastic activity in both in vitro and in vivo studies [9,22,25,27].
Pairing artemisinin or its semisynthetic derivatives with other anti-cancer agents could result in effective treatments for leukemia and related diseases. The present application reports on the results of experimental investigations into such combination therapies and new methods for treating cancer developed therefrom, along with other important matters.